Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 17 Micro encapsulation of Naproxen By Complex Coacervation and Aqueous Colloid Dispersion Part ( 1 ) Ahmad N.Abood *, Yehia I. Khalil** 1 *De partm en t Ph arm ace utics ,Co lle ge o f Pha rm a cy , Un iv ersity of Bashra, B ashra-Iraq **D epartme nt o f De pa rtm en t P harmaceu tic s, Colleg e of P harm ac y, Unive rsity ofBag hda d, Bag hda d-Iraq Ab stract Naproxen is a non s te roida l anti inflammatory and a ntipyre tic drug which has loca l irritation effe ct on the s tomach, and unplea sant ta ste, beside s bad flowability a nd light se nsitivity .The drug was pre pared a s mic roc aps ules by c omplex c oac ervation method using aca cia-gelatin coa ting materials , and aqueous c olloid polymer dis persion me thod ( ACPD ), using e thyl ce llulose and s odium alginate coa ting materials . The res ults indica te d tha t mic rocapsules prepared by 2:1 core:wall ratio is the bes t for both me thods , with a n ave ra ge enc aps ulation efficienc y (75%) and avarege yield (90%) . More ove r the drug releas e was affected mainly by c ore : ra tio ,pH envirome nt a nd method of mic roenc aps ulation . K ey words: Na proxe n,Microc aps ule , Aque aus c olloid polymer dispersion الخالصة مستساغ غير وطعم للمعدة مخدشة اعراض ذو للحرارة وخافض لاللتهابات مضاد ستيرويدى غير عقار هو النابروكسين مجهرية كبسوالت شكل على العقار تحضير تم لقد بالضوء الشديد تاثره الى اضافة التصييغ اثناء جريانه فى وصعوبة اضافة االثيلى والسيلليلوز الجيالتين العربى كالصمغ مختلفة مواد باستعمال المائى واالنتشار المعقد التقوصر بطريقتى وناتج ۷٪ تحميل بمعدل االفضل كانت المغلفة المادة الى اللبية المادة من١ :٢ نسبة ان وجد لقد الصوديوم الجينات الى ونسبة التحضير بطريقة المجهرية الكبسوالت هذه من كبير بشكل العقار بتأثرتحرر النتائج اظهرت كما ٪ ۹۰ بلغ نهائى . البيئى للوسط الهايدروجينى االس ال اضافة المغلفه المادة ال اللبية المادة In troduction The principle of mic ro enc ap sulation is fo rma tio n o f a thin co ating of wa ll materia l around the s ub stance, therefore ma king the pa rtic le s more des ira bl in te rms o f physica l and che mic al p ro pertie s (1,2) , the quantity o f drug inco rpo ra tion a s a core materia l vary from 20 -9 5% (3) Na proxe n is a ryl ac etic acid group d eriv ative of non-s te ro id al a nti infla mmatory d rugs wid ely use d in rheumatoid arthritis and ankylo sing sp ond ylitis (4) .The ma in s id e effe cts of this drug a re GIT disturba nc es a nd bitte r tas te . The go als o f this s tudy are to mask the irritation effect of the a ctive drug to the GIT, and imp rov e physica l prop erties o f the drug like flowa bility and light se ns itivity Experime nta l Mater ials : Nap ro xen powd er s up plie d by Sa marra " Drug Industery (SDI) ,a cac ia,gelatin,ethyl ce llulos e,so dium algina te ,c alcium chlo ride ,formalde hyd e,from Ried el De -Ha en AG;See lze,Hanno ver, Ge rmany All othe r reagents a re of a n ana lytic al gra de . Ins trume nts : sa rtorius ba la nc e,type 121 9 MP3 , e le ctrica l stirrer Ike - Werk typ e Re- 16 , (Ge rma ny) , ove n , mammert 854 Sc hwa Ba ch, (Ge rma ny) , micros cop e, Olympus CX21 Tokyo Ja pa n,Cintra 5 GBC,UV-Vidible spe ctome te r, d is so lution ap paratus Erweka USP DT6 Ha ns en (Germany) , water b ath pH- me ter (W-Ge rma ny) . Pre par atio n o f n apr oxe n micr oca ps ule s (c omplex c oac er vation) The microc aps ules w ere pre pa re d by incorpo ra ting nap ro xen powd er in 50 ml.o f 2% w/w aca cia s olution previously hea te d to 40C, the n 50 ml. of gelatin so lution 2 %w/w a t 40C was ad ded a nd ma inta ined at 250 rpm stirring spe ed for 50 minute s ,a djus ting the pH of mixture to 4 with fe w drop s o f diluted HCL(0.1M),the formatio n o f mic ro ca psule s can b e watched micro sc opica lly ,then 10 ml. of fo rmaldehyde s olutio n wa s a dd ed w ith continuous stirring fo r 10 minute s, c oo ling in ic e bath , filtered the microc aps ules fo rmed using three portio ns of 100 ml. iso propyl alcohol a nd then the wetted mic ro ca psule s were drie d before the fre e flowing p owd ered mic ro cap sule s ob ta ined (5) . 1corresp ond in g author email ybmma z@ yahoo .com Rece ived 2 5-12-20 05 Acce pted 2 5-7 -2 006 Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 18 Pre pa ration o f n apr oxe n micr oca ps ules ( ACPD me th od ) The d rug was d is pers ed in 50ml. o f 2% w/w aq ueo us so dium algina te s olutio n hea te d to 40C , the n 50ml. of 3 0% w/w ethyl c ellulo se prepa re d at ro om te mpe ra ture wa s ad de d with co ntinous s tirring , (the weight of naproxen ad ded d epe nd on c ore:wall ratio o f microca psule s prepa re d ) .The mixture was allo wed to drop through mod ified se paratory funnel into gently agitate d c alcium chloride (1 % w/w ),the gelled be ad s w ere s ep arated after 2 minutes b y vac cum filteration, rins ed with d is tille d water a nd a llow to dry a t 40C ove r night (6) .All the microc aps ules rep ared by bo th two me thods we re o f 1:2 ,1:1 a nd 2:1 core : wall ratio whic h c orre spo nd s to 33.3 % ,50 % a nd 6 6.6% drug c ontent re sp ectively. Dis so lu tion b eha viour F or a ll type s of mic ro ca psule s prep ared under sink c ond itions ,the d is so lution b ehaviour o f nap ro xen was ca rrie d o ut us ing 10 0mg. equiv alent do se in 9 00ml. of different disso lutio n medium pH (1.2,4.2 a nd 6.8 ) a t 37 + 0.5C and c onstant stirring spe ed of 50 rp m , Then filtered sa mples we re take n fo r ana lysis at different sp ecifie d time intervals , The ab sorba nce of e ach sa mple wa s determine d s pe ctro pho to metric ally a t 272 ,33 0 ,a nd 2 71 nm. re sp ective ly . Results a nd Dis cussions Pre par atio n of micr oc aps ules : Tab le 1. ( A and B ) illus trates the yield perce nt a nd the e nca ps ulatio n efficiency of nap ro xen by diffe re nt p re pa ra tion me thod s and core: wall ratio s, it w as found that coa ce rva tio n method gave 75-85 % yield comp ared with 8 6-93% giv en by ACPD metho d ,while e nc aps ulation effic ie ncy wa s 48-82 % a nd 27 -7 0% fo r co mplex c oa cerva tion and ACPD metho d , res pec tive ly . Ta ble (1)Effect of varia tion o f co re to wall ratio of naproxe n micro ca psule s on the microe ncapslation by :-A- Co mple x co acervatio n me thod Mic roe nc ap Sulation Effic ie ncy Drug lo ading % % Yie ld Microe nca p Sula tion y ie ld Core To Wa ll ratio Ac tua l (gm) Theore tical (gm) Ac tual (g m) Theore tical (gm) 81.9 54.6 6 6.6 8 5.4 10 .2 5 12 2 :1 7 5 37.5 50 7 7.5 6 .2 8 1 :1 48.5 16 .1 7 3 3.3 75 4 .5 6 1 :2 B- Aque o us c ollo idal poly me r dispe rs ion me tho d The res ults indicated tha t be st e nca ps ulatio n effic ie ncy was in c omp le x co ace rv atio n co mpared with ACPD method ,which may b e attribute d to the ability of po lymer used to encap sula te the drug (6) . On the othe r hand the results reve aled that encap sula tion e fficienc y ap pea re d to b e c ore weight de pendent , Higher p erce nt of d rug lo ad ing w as shown with 2 :1 c ore wa ll ra tio The se res ults a re co ns is te nt with the re sults obta ined in c ase of me tronid azol (7) and chlo ra mphe nico l mic ro ca psule s (8). mo reo ve r the a pprec ia ble amounts of microca ps ule gaine d (8 6 - 93%) b y ACPD me thod may b e re fe rred to the c ompa tib ility b etwee n na pro xe n and po lymer use d , s ince bo th o f them are acidic in na ture (9). Dis so lu tion be haviour o f micro ca psu le s: Figure 1 and 2 s ho ws the re le ase p ro files of nap ro xen from 2 :1 co re wa ll ratio mic ro cap sule s fo r bo th metho ds of prep aratio n at p H 6.8 and 1 .2 re spe ctiv ely. Core to wall ratio Microe nca p sulation yie ld % y ie ld Drug load ing % Microe nca p s ulatio n efficie ncy (%) Theo retical (gm) Actua l (gm Th eo re tical (g m) Ac tual (gm 2 :1 7 0 46.6 66.6 93 1 4 15 1 :1 6 0 30 50 85 8 .5 10 1 :2 2 7 9 33.3 86 6 .5 7.5 Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 19 0 20 40 60 80 100 120 Time (min) 0 5 10 15 20 25 30 P e rc e n t of d ru g r e le a se 2: 1 core to wall ratio 1:1 core to wall ratio 1: 2 core to wal ratio It wa s fo und that in comple x coa ce rv atio n metho d , the relea se was ; fas te r tha n in ACPD metho d at p H 6 .8 , sinc e t5 0% of d rug re le as e to oko ver 8 minutes for firs t metho dc ompa re d with 75 minutes for the later, these res ults are consistent with the res ults ob ta ined b y mic ro enc ap sula tion o f diclofenac s odium (10) and p ro te in (1). The drug relea se at p H 1.2 ; d ecrea se d signific antly fo r bo th me thod (not mo re tha n 30% at first two hours) , this be ha viour may b e attributed to the nature of nap ro xe n diss olutio n at low pH (12 ) . On the othe r ha nd the e ffec t of core wa ll ratio on the relea se o f na proxe n fro m mic ro cap sule s was s hown in figures 3 and 4 , It was s ee n that high significant diffe re nc e (p < 0.00 1) in the p erce nt drug releas e afte r 120 minute s betwee n 2 :1 a nd 1 :2 core wa ll ra tio s (c oac ervation me thod) , the ca use is referre d fo r both drug co ntent and s olve nt pe ntratio n and this in co ns is te nt with the res ults o btaine d by the s tudy of d is solution of diazep am mic ro cap sule s (13) . 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 120 140 160 180 200 220 Time(min) P e rc e n t o f d ru g r e le a se Complex coacervation 2:1 ACPD 2:1 0 10 20 30 0 10 20 30 40 50 60 70 80 90 100 110 120 Time(min) P e rc e n t o f d ru g r e le a s e Complex coacervation 2:1 ACPD 2:1 Figure (1) : Effe ct o f me thod o f microe ncapsula tion o n the re lease o f na proxe n fro m mic roc aps ules in phos pha te buffe r pH 6 .8 . Fig ure (2 ): Effe ct of me thod o f microe nca ps ulatio n on t he re lease of naproxe n from mic ro capsule s in 0 .1N HCl pH 1.2 . Figure (3): Effe ct o f va rying c ore -wall ra tios on the re le ase of naproxe n fro m microcaps ules pre pare d by comple x coace rv atio n me thod in 0.1N HCl pH 1 .2 . Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 20 0 20 40 60 80 100 120 Time (min) 0 5 10 15 20 25 30 35 40 P e rc e n t o f d ru g r e le a s e 2: 1 core to wall ratio 1:1 core to wall ratio 1: 2 core to wal ratio 0 20 40 60 80 100 120 Time (min) 0 10 20 30 40 50 60 70 80 90 100 P e rc e n t of d ru g r e le a se Phosphate buffer (pH 6.8) Acetate buffer (pH 4.2) 0.1N HCl (pH 1.2) 0 20 40 60 80 100 120 Time (min) 0 10 20 30 40 50 60 70 80 90 100 P e rc e n t o f d ru g r el ea se Phosphate buffer (pH 6.8) Acetate buffer (pH 4.2) 0.1N HCl (pH 1.2) 0 20 40 60 80 100 120 Time (min) 0 10 20 30 40 50 60 70 80 90 100 P e rc e n t of d ru g r e le as e Phosphate buffer (pH 6.8) Acetate buffer (pH 4.2) 0.1N HCl (pH 1.2) The s ame res ulte s were ob tained from mic ro ca psules prepared by ACPD metho d , since 40,24 a nd 20 % o f drug released from mic ro ca psules fro m 1 :2 , 1:1 and 2:1 core wa ll ra tio respec tively . In a n atte mpt to stud y the e ffec t of d ifferent pH-med ium o n the release o f nap ro xe n from thes e microc apsules, figures 5 to 10 were co nstruc te d for both coa ce rvatio n and ACPD metho ds . Figure (4 ): Effe ct of va ry ing core -wall ra tios o n the re le ase o f naproxe n from microca ps ules pre pare d by ACPD me thod in 0.1N HCl pH 1 .2 . Figure (5): Effe ct o f pH on the re lease of naproxe n from 1:2 c ore-wall ra tio microca psule s pre pare d by c omple x c oace rvation me tho d Fig ure (6): Effect of pH o n the re le ase of naproxe n fro m 1:1 core - wall ratio microc aps ules pre pare d by c omple x c oace rvation me tho d. Figure (7 ): Effect of pH on the re lease of napro xe n from 2:1 co re -wa ll ratio mic ro capsule s pre pa re d by comp le x coace rv atio n me thod. Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 21 0 20 40 6 0 80 10 0 1 20 1 40 Time (min) 0 10 20 30 40 50 60 70 80 90 1 00 P e rc e n t o f d ru g r e le a s e Pho sp h ate bu f fer ( p H 6 .8) Ace tat e b u ff er ( pH 4.2) 0.1N HC l 0 20 40 60 80 100 120 140 160 180 200 220 Time (min) 0 10 20 30 40 50 60 70 80 90 100 P er ce n t of d ru g r el e as e Phosphate buffer (pH 6.8) Acetate buffer (pH 4.2) 0.1N HCl 0 2 0 40 60 8 0 1 0 0 12 0 1 40 1 60 1 8 0 T im e (m in ) 0 10 20 30 40 50 60 70 80 90 1 00 P e rc e n t o f d ru g r e le a s e P h o sp h at e b u ff e r ( p H 6.8 ) A c et at e b u ff er ( pH 4.2 ) 0 .1 N HC l . The res ults s howe d tha t the re are high s ignific ant differences (p < 0.00 1) in t5 0% d rug re le ase fro m d ifferent c ore wall ra tios p re pa re d b y coa cerva tion me thod at pH 1 .2 a nd 4 .2 in c ompa riso n with p H 6 .8 (microc aps ules pre pa re d by coa cerva tion method a t p H 1 .2 a nd 4 .2 ) The s ame results were re cognize d for the s ame core: wall ratios microc aps ules p re pared b y ACPD me thod , the se res ults are the s ame res ults obta ined in the eva luation of s ulfona mid e ,ibup ro fe n (14),a nd me fe na mic a cid microca ps ules (15) . Conclusion Base d o n the res ults ob ta ined , one may c onclude s the follo wings . a . Both comp le x c oa cerva tion and ACP D method s are valid for mic roe nc aps ulation of nap ro xen. b . The diss olution be ha viour of naproxen fro m mic ro cap sule s is affecte d by pH- medium ,co re :wa ll ratio and prepa ra tion method s. c . The re sults obta ined in this s tudy c ould be use d to formulate naproxen in many mic ro enc aps ulated dos age fo rms . Refe renc es 1. Anse l ll.C., Alle n L.V.J R.Pop ovich N.G ., Pha rma ce utic al d os age fo rms a nd d rug delivery system . I ipp inco ll Williams and Wilkins ,8th e dition,200 5 , Se ctio n III , chapter 9,765 ,2 67. 2. S ha rgel L., And re w Y ., Ap plie d Bio pha rmace utic s and pharmac okinelic s 4 th editio n 199 9,chapter 7 ,168 . 3. Racz l ., S c.C. chem. , drug fo rmula tio n , 198 9chapte r 4,36 4. 4. USP , XXIII , The united sta le s pha rma co poe ia ,19 95 . 5. Curt theis ,Asurve y of microe nca ps ulatio n proce ss es , In : Simo n Benila (ed ) mic ro enc ap sulation metho ds and industrial app lica tions , Marce l Dakker ,Inc .New York ,1 996 . 6. J izomo to H., Ka na oka E. a nd S ugita K., Gelatin ac ac ia microca psules fo r tra pp ing mic ro o il d ro plets co ntaining lipop hilic drugs and rea dy d is inte gratio n in the ga stro inte stinal trac t , P harmac eutica l Re sea rc he s 199 3,10,11 15-11 120 . 7. Al-os ta H.A., mic ro enc ap sulation of metro nidazole as solid dos age fo rm , thes is for M.Sc . degre e , c olle ge of p ha rma cy , Unive rs ity of Baghda d , 2 000 . 8. Ali W.K., Re leas e of chloramp he nicol from the pre pa re d microc ap sules the sis fo r M.S c degre e , co llege of pharmac y , Unive rs ity of Baghda d 198 9 . 9. El- Giba ly I ., Sa fwa t S.M . a nd Ahme d M.O ., microe nca ps ulatio n of ketop ro fe n us ing Figure (8): Effe ct of pH o n the re le ase o f naproxe n from 1:2 c ore-wall ra tio mic ro capsule s pre pa re d by ACPD me thod Figure (9 ): Effect o f pH on the re lease of na pro xe n from 2 :1 co re . wa ll ratio microca psule s pre pare d by ACPD me thod. Figure (10): Effe ct o f pH on the re lease o f na proxe n from 1:1 co re - wall ratio mic roc aps ules pre pare d by ACPD me tho d Iraqi J.Pharm.Sci., Vol.15 (2) ,200 6 Micro Enca psulatio n of Na proxen part (1) 22 w/o /w co mplex emulsion technique ,bulletin of p ha rma ceutic al s ciences ,As siut univ ersity , de partment o f indus trial Pharmac eutics ,17 Feb ruary ,147 – 1 63 ,199 1 . 10. Chowd ary K.P and S as try V.II ., microencap sula tion o f dic lo fnac- comp aris io n of d rug relea se fro m va rious mic ro ca psule s ea stern pharmac is ts 1 997 , 4 0 Sep tembe r ,119 - 122 . 11. Gombo tz W.R .and We e S.F .re le ase from algina te matric es , a dv anc ed drug d eliv ery re views ,3 1 May ,267 -285 ,1 998 . 12. Aulto n M.E., Pharmac eutics the s cienc e of dos age fro m de sign , Churrchil liv ing stone ,2 nd editio n ,2 002 . 13. 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